This SBIR Phase I proposal is intended to demonstrate the feasibility of developing a novel and effective therapeutic approach that can save lives of people with radiation injury. Acute radiation injury may occur in various incidents as well as the terrorist radiation exposure scenario. Acute radiation syndrome develops after whole-body or a partial-body irradiation with a high dose of radiation. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific treatment approaches to acute radiation injury. As such, there is an urgent unmet medical need for an effective novel mitigator for patients with acute radiation injury. Ghrelin, a gastrointestinal peptide, was first identified as an endogenous ligand for the growth hormone secretagogue receptor type 1a (i.e., ghrelin receptor). Ghrelin was originally reported to induce growth hormone release through stimulation of ghrelin receptors in the central nervous system. A large body of evidence has indicated other physiological properties of ghrelin mediated by the central and peripheral ghrelin receptors. Although human ghrelin has been shown to be beneficial in certain disease conditions, it remains unknown whether this peptide can mitigate acute radiation syndrome. To study this, adult male rats were exposed to 10-Gy total body irradiation (TBI). Our preliminary data have shown that administration of human ghrelin 6 h after TBI (i.e., very early treatment) reduced mortality. However, it remains unknown whether delayed administration of human ghrelin (which is more clinically relevant) reduces TBI-induced mortality as well. We, therefore, hypothesize that delayed administration of human ghrelin after TBI attenuates tissue injury and improves survival. The primary objective of this SBIR Phase I project is targeted towards demonstrating the feasibility of the development and commercialization of human ghrelin as an effective mitigator (24 h post-radiation or later) in reducing the massive mortality after acute radiation exposure scenario. The optimal dosage(s) of human ghrelin (delayed treatment) will be determined by assessing 1) the dose-response effect of ghrelin tissue injury after TBI;2) the dose-response effect and time-course of human ghrelin on TBI-induced mortality;and 3) the pharmacokinetics of human ghrelin in healthy and irradiated animals. Our ultimate goal (SBIR Phase II and beyond) is to obtain commercial utilization of human ghrelin as a safe and effective mitigator for people with acute radiation injury. PUBLIC HEALTH RELEVANCE: In the wake of the September 11, 2001 terrorist attacks, the misuse of ionizing radiation or nuclear devices as weapons of terrorism has been recognized as a major public health threat. Despite advances in our understanding of the pathophysiology of acute radiation injury, the management of acute radiation syndrome is mainly supportive. Very little information is available on the specific therapeutic approaches to radiation injury. Thus, there is an urgent unmet medical need for a novel and effective mitigator for people with acute radiation injury.